Gastric aspiration is a major risk factor for the development of ARDS, and also places the patient in jeopardy of secondary bacterial pneumonia. The major objective is to examine cellular mechanisms that increase the risks of these diseases. Although aspiration-induced host changes are poorly understood, this laboratory has demonstrated a likely role for TNF-alpha, IL-1-beta, MIP-2, MCP-1, and toxic inflammatory chemical mediators including proteinases, oxidants, and nitric oxide (NO) in the pathogenesis of the secondary lung injuries. The applicants hypothesize that increased susceptibility results from acid-induced, cytokine-mediated "priming" of leukocytes. They have demonstrated that "priming" enhances release of oxidants, NO, and proteinases following an additional sustained insult. They predict that oxidants and NO can subsequently augment cytokine progression and accelerate the shift to monocytic recruitment, thereby increasing lung injury and mortality. Aims #1 and #2 will focus on mechanism(s) involved in "priming" and Aim #3 will evaluate the effects of "priming" on susceptibility of the host to bacterial infection. Aim #1 will assess: a) recruitment and turnover of the MO population following acid (ACID), small non-acidified particle (SNAP), or combined acid small particulate (CASP) aspiration and b) in vivo TNFalpha and/or IL-1beta, or MCP-1 neutralization on the ability to reverse alterations in ex vivo MO expression of cytokines, iNOS, and MO toxic products. The investigators predict that CASP aspiration will augment the progression of the cytokine response to a more rapid expression of MCP-1 and MO influx with enhanced effector activity. Aim #2 will examine the role of superoxide, H2O2 and/or NO to the CASP-induced synergistic lung injury and increased mortality by examining the proinflammatory cytokine cascade and leukocyte influx following: a) selective inhibition of superoxide, H2O2, or NO generation, before or following CASP aspiration, or b) hyperoxia-induced generation of oxidants and/or NO following ACID aspiration. They postulate that increased H2O2 and NO generation will augment the progression of proinflammatory cytokines and accelerate the appearance of MCP-1-mediated monocyte recruitment. Finally, in Aim #3 they will examine cytokine expression, lung inflammatory cell influx, bacterial clearance, lung injury, and mortality following gastric aspiration. The investigators anticipate that aspiration will increase the lung injury to bacterial challenge by initially enhancing the inflammatory injury, but eventually impairing TNFalpha, IL-1beta, and/or MIP-2 production, thereby decreasing bacterial clearance. These studies may uncover mechanisms on which to base therapeutic strategies.